Preparation method of solvent-free water-dispersible hydroxypropyl methyl cellulose phthalate nanoparticle

ABSTRACT

The present invention relates to a preparation method of solvent-free water-dispersible hydroxypropyl methyl cellulose phthalate nanoparticle, and more particularly, to a preparation method of solvent-free water-dispersible hydroxypropyl methyl cellulose phthalate nanoparticle, which is environment-friendly and advantageous in disintegration and dissolution when used as an enteric coating material, which is prepared by obtaining suitable hydroxypropyl methyl cellulose phthalate (HPMCP) particle through aqueous emulsification process and regulating content of remaining electrolyte through ion exchange process.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national phase of international application numberPCT/KR01/02015, filed Nov. 22, 2001, the content of which isincorporated herein by reference and claims the priority of KoreanPatent Application No. 2001/70966, filed Nov. 15, 2001.

FIELD OF THE INVENTION

The present invention relates to a preparation method of solvent-freewater-dispersible hydroxypropyl methyl cellulose phthalate nanoparticle,and more particularly, to a preparation method of solvent-freewater-dispersible hydroxypropyl methyl cellulose phthalate nanoparticle,which is environment-friendly and advantageous in disintegration anddissolution when used as an enteric coating material, which is preparedby obtaining suitable hydroxypropyl methyl cellulose phthalate (HPMCP)particle through aqueous emulsification process and regulating contentof remaining electrolyte through ion exchange process.

Until now, mainly hydroxypropyl methyl cellulose phthalate and acrylatehave been used as enteric coating materials. However, for hydroxypropylmethyl cellulose phthalate, organic solvent is used during coatingprocess, which may cause environmental problem. And, for acrylate,although the water-dispersible product is available, it is a syntheticpolymer rather than a natural material and it has poor film propertiescompared to those of hydroxypropyl methyl cellulose phthalate.Therefore, need of a new type of environment-friendly material has beenincreased.

In this regard, water-dispersible hydroxypropyl methyl cellulosephthalate has been prepared. The conventional method of preparing thiswater-dispersible hydroxypropyl methyl cellulose phthalate comprises:completely dissolving hydroxypropyl methyl cellulose phthalate withorganic solvent and dispersing it in water; removing organic solvent inthe solution to obtain water-dispersible type of hydroxypropyl methylcellulose phthalate. However, the product obtained by this method haspoor stability in water-dispersible phase. Further, the use of anorganic solvent incurs an increase in manufacturing cost, and it alsohas a drawback that the organic solvent is hardly removed from the finalproduct thereby causing an environmental problem.

U.S. Pat. No. 5,560,930 discloses a method of preparing particle ofabout 0.2% by emulsifying hydroxypropyl methyl cellulose phthalate inwater after dissolving it in acetone and removing the organic solventthrough distillation under reduced pressure. It discloses examples ofusing a solvent mixture, such as ethanol/water and methanol/water. U.S.Pat. No. 5,512,092 discloses a method of dissolving hydroxypropyl methylcellulose phthalate in ethanol and emulsifying it; and U.S. Pat. No.5,346,542 discloses a method of dissolving carboxymethyl ethyl cellulosein methyl acetate and emulsifying it in water. Although these methods donot have problems of latex particle size or dispersion, productstability after emulsification is poor and leaves the organic solvent inthe final product because it is difficult to remove organic solventremaining in the solution. We prepared water-dispersible hydroxypropylmethyl cellulose phthalate according to the above method in 1 cm×1 cmfilm. When it was placed in aqueous solution of pH 1.2 for 2 hr, thefilm was dissolved. And, we diluted this water-dispersible hydroxypropylmethyl cellulose phthalate to 7 wt % with distilled water and coated iton the tablet using Hi-Coater (HCT Labo, Freund Co.). The disintegrationtest (Pharmatest PTZ E) showed that disintegration took place in 2 hrunder pH 1.2. Because of this, commercialization of water-dispersiblehydroxypropyl methyl cellulose phthalate has not been achieved as yet.

SUMMARY OF THE INVENTION

In order to solve these problems, we prepared stable particles byintroducing aqueous emulsification process of hydroxypropyl methylcellulose phthalate (HPMCP) without using an organic solvent. And, weregulated the amount of remaining electrolytes through ion exchangeprocess in order to obtain hydroxypropyl methyl cellulose phthalate.

Accordingly, an object of the present invention is to provide apreparation method of solvent-free water-dispersible hydroxypropylmethyl cellulose phthalate nanoparticle, which is environment-friendlyand advantageous in disintegration and dissolution without having theproblem of leaving the organic solvent in the final product.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is characterized by a preparation method ofsolvent-free water-dispersible hydroxypropyl methyl cellulose phthalatenanoparticles, which comprises:

-   -   1) a step of emulsifying hydroxypropyl methyl cellulose        phthalate at 20-70° C. for 4-6 hr using emulsifying agent and        NH₄OH; and    -   2) an ion exchange step of reducing content of electrolyte        remaining in hydroxypropyl methyl cellulose phthalate obtained        by the step 1) to 050 mS using ion exchange resin or membrane.

Hereunder is given a detailed description of the present invention.

The present invention is characterized by a preparation method ofwater-dispersible hydroxypropyl methyl cellulose phthalate nanoparticlestable in water, by neutralizing a phthalate group of hydroxypropylmethyl cellulose phthalate with NH₄OH and controlling electrolytecontent remaining in the solution through ion exchange process.

Hereunder is given a more detailed description of the present invention.

Firstly, the step 1 is a step of forming water-stable particle byemulsifying hydroxypropyl methyl cellulose phthalate at 20-70° C. for4-6 hr using an emulsifying agent and NH₄OH. For hydroxypropyl methylcellulose phthalate, the one with 40,000-60,000 of mean molecular weightcan be used. And as an emulsifying agent, Pluronic F-68, Triton X-405,Tween-80, Polystep B-1 or Polystep F-9 can be used. The emulsifyingagent is preferred to be used in 0.05-1.0 wt % against hydroxypropylmethyl cellulose phthalate. If its content is below 0.05 wt %, stabilityof water-stable HPMCP is deteriorated; and if it exceeds 1.0 wt %, filmproperty is lowered when it is coated on tablet. For neutralizer, NH₄OHcan be used. Its content is preferred to be 1.6-4.0 wt % againsthydroxypropyl methyl cellulose phthalate. If it is below 1.6 wt %, therecan arise a stability problem because particle size is enlarged; and ifit exceeds 4.0 wt %, the tablet may give off ammonia-like odor due toexcess use of NH₄OH. In particular, it is preferred to use 28% NH₄OHsolution.

The step 2 is an ion exchange step to regulate remaining electrolytecontent to 0-50 mS by using ion exchange resin or membrane. If theremaining electrolyte content is above this range, excess amount of ionexchange resin has to be used to remove the remaining electrolyte. Forion exchange resin, cation exchange resin, e.g., Dowex MR-3(Sigma-Aldrich, US) can be used. For membrane, it is recommended to usethe one with pores of 100-300 nm in size. If the pore size is below 100nm, a considerable amount of time is required to remove remainingelectrolyte; and if it exceeds 300 nm, the HPMCP particle may penetratethe membrane, which may cause reduction of solid content. Here, theremaining electrolyte means the ammonium ion which forms salt, and itaffects physical properties of hydroxypropyl methyl cellulose phthalate.

The present invention includes water-dispersible hydroxypropyl methylcellulose phthalate prepared by said steps 1 and 2. The obtainedwater-dispersible hydroxypropyl methyl cellulose phthalate has 100-1000nm of particle size and contains 7-30 wt % of solid contents.

The hydroxypropyl methyl cellulose phthalate prepared by the presentinvention shows no particle sedimentation when stored for long time inwater and does not dissolve in pH 1.2 when it is coated on tablet.Therefore, it can be used as environment-friendly enteric coatingmaterial.

The following examples are intended to be illustrative of the presentinvention, and they should not be construed as limiting the scope ofthis invention.

EXAMPLE 1

400 g of distilled water, 1.0 g of Pluronic F-68 and 100 g ofhydroxypropyl methyl cellulose phthalate (Mw 40,000-60,000, Samsung FineChemicals Co., Ltd. Brand name with AnyCoat-P) were placed in 1L reactorequipped with a stirrer and stirred at 300-350 rpm. 28%-NH₄OH (8 g) wasslowly added to this solution and the temperature was raised to 60° C.After stirring for another 4-5 hr while maintaining the temperature, theremaining ammonium ion concentration was regulated to 0.0-7 mS using ionexchange resin [Dowex MR-3, Sigma-Aldrich, US].

The prepared water-dispersible hydroxypropyl methyl cellulose phthalatehad 4.6±1.0 of pH, 25±5% of solid content, 140±5 of acid value and300±50 nm of particle size.

The pH was measured with a pH meter of Orion research, Inc. and thesolid content was measured by gravimetric determination. The acid valuerepresents distribution of a carboxyl group per unit surface area. 0.1 NKOH was used to determine the acid value; and THF and methanol were usedto dissolve dry sample. The particle size was measured by dynamic lightscattering (DLS; Zetaplus, Brookhaven Instruments).

The obtained water-dispersible hydroxypropyl methyl cellulose phthalatewas made into 1 cm×1 cm film and placed in pH 1.2 of an aqueoussolution. When it was taken out after 2 hr, it remained in shape withoutbeing dissolved. The water-dispersible hydroxypropyl methyl cellulosephthalate was diluted to 7 wt % with distilled water and coated ontablet using Hi-Coater (HCT Labo) The disintegration test (PharmatestPTZ E) showed that no disintegration took place for 2 hr under pH 1.2.

EXAMPLE 2

400 g of distilled water, 0.53 g of Triton X405 and 106 g ofhydroxypropyl methyl cellulose phthalate (Mw 40,000-60,000, Samsung FineChemicals Co., Ltd.) were put in 1L reactor equipped with a stirrer andstirred at 300-350 rpm at room temperature. 28%-NH₄OH (10 g) was slowlyadded to this solution and it was stirred for another 4-5 hr. Theremaining ammonium ion concentration was regulated to 0.0-7 mS using ionexchange resin [Dowex MR-3, Sigma-Aldrich, US].

The prepared water-dispersible hydroxypropyl methyl cellulose phthalatehad 4.8±1.0 of pH, 19.9% of solid content, 145 of acid value and 700:50nm of particle size.

The obtained water-dispersible hydroxypropyl methyl cellulose phthalatewas made into 1 cm×1 cm film and put in pH 1.2 of an aqueous solution.When it was taken out after 2 hr, it remained in shape without beingdissolved. The water-dispersible hydroxypropyl methyl cellulosephthalate was diluted to 7 wt % with distilled water and coated on atablet using Hi-Coater (HCT Labo). The disintegration test (PharmatestPTZ E) showed that no disintegration took place in 2 hr under pH 1.2.

EXAMPLE 3

400 g of distilled water, 0.7 g of Polystep B-1 and 100 g ofhydroxypropyl methyl cellulose phthalate (Mw 40,000-60,000, Samsung FineChemicals Co., Ltd.) were placed in a 1L reactor equipped with a stirrerand stirred at 300-350 rpm at room temperature. 28%-NH₄OH (11.5 g) wasslowly added to this solution and it was stirred for another 4-5 hr. Theremaining ammonium ion concentration was adjusted to 0.0-7 mS usingmembrane (pore size: 200 nm). Because emulsifying agent is removedtogether with the remaining ammonium ion, the emulsifying agent wasreplenished continuously so as not to alter the emulsifying agentconcentration.

The prepared water-dispersible hydroxypropyl methyl cellulose phthalatehad 8 ±0.5 of pH, 20.0% of solid content, 140 of acid value and 100±50nm of particle size.

The obtained water-dispersible hydroxypropyl methyl cellulose phthalatewas made into 1 cm×1 cm film and placed in pH 1.2 of an aqueoussolution. When it was taken out after 2 hr, it remained in shape withoutbeing dissolved. The water-dispersible hydroxypropyl methyl cellulosephthalate was diluted to 7 wt % with distilled water and coated ontablet using Hi-Coater (HCT Labo). The disintegration test (PharmatestPTZ E) showed that no disintegration took place in 2 hr under pH 1.2.

EXAMPLE 4

400 g of distilled water, 0.5 g of Tween-80 and 100 g of hydroxypropylmethyl cellulose phthalate (Mw 40,000-60,000, Samsung Fine ChemicalsCo., Ltd.) were placed in a 1L reactor equipped with a stirrer andstirred at 300-350 rpm. 28%-NH₄OH (8 g) was slowly added to thissolution and the temperature was raised to 60° C. After stirring foranother 4-5 hr while maintaining the temperature, the remaining ammoniumion concentration was adjusted to 0.0-7 mS using ion exchange resin(Dowex MR-3, Sigma-Aldrich, US).

The prepared water-dispersible hydroxypropyl methyl cellulose phthalatehad 4.6±1.0 of pH, 25±5% of solid content, 140±5 of acid value and500±50 nm of particle size.

The obtained water-dispersible hydroxypropyl methyl cellulose phthalatewas made into 1 cm×1 cm film and placed in pH 1.2 of an aqueoussolution. When it was taken out after 2 hr, it remained in shape withoutbeing dissolved. The water-dispersible hydroxypropyl methyl cellulosephthalate was diluted to 7 wt % with distilled water and coated on atablet using Hi-Coater (HCT Labo). The disintegration test (PharmatestPTZ E) showed that no disintegration took place in 2 hr under pH 1.2.

EXAMPLE 5

400 g of distilled water, 0.65 g of Polystep F-9 and 106 g ofhydroxypropyl methyl cellulose phthalate (Mw 40,000-60,000, Samsung FineChemicals Co., Ltd.) were placed in a 1L reactor equipped with a stirrerand stirred at 300-350 rpm at room temperature. 28%-NH₄OH (10 g) wasslowly added to this solution and it was stirred for another 4-5 hr. Theremaining ammonium ion concentration was adjusted to 0.0-7 mS using ionexchange resin (Dowex MR-3; Sigma-Aldrich, US).

The prepared water-dispersible hydroxypropyl methyl cellulose phthalatehad 4.8±1.0 of pH, 19.9% of solid content, 145 of acid value and 200±50mm of particle size.

The obtained water-dispersible hydroxypropyl methyl cellulose phthalatewas made into 1 cm×1 cm film and put in pH 1.2 aqueous solution. When itwas taken out after 2 hr, it remained in shape without being dissolved.The water-dispersible hydroxypropyl methyl cellulose phthalate wasdiluted to 7 wt % with distilled water and coated on a tablet usingHi-Coater (HCT Labo). The disintegration test (Pharmatest PTZ E) showedthat no disintegration took place for 2 hr under pH 1.2.

COMPARATIVE EXAMPLE 1

U.S. Pat. No. 5,560,930 discloses the following method. 0.3 kg ofhydroxypropyl methyl cellulose phthalate dissolved in 9.7 kg of acetoneis emulsified in 10 kg of distilled water while stirring at 100 rpm. Theprepared emulsion is distilled under reduced pressure under thecondition of 50° C./−590 mm to remove an organic solvent.

However, when we followed this procedure, although there was no problemof latex particle size or dispersion, there was a problem of productstability after emulsification and it was difficult to remove theorganic solvent. Especially, the organic solvent remained in the finalproduct. We also made 1 cm×1 cm film with the obtained water-dispersiblehydroxypropyl methyl cellulose phthalate and put in pH 1.2 of an aqueoussolution. When it was taken out after 2 hr, the film had been dissolved.Also, we diluted the water-dispersible hydroxypropyl methyl cellulosephthalate to 7 wt % with distilled water and coated it on a tablet usingHi-Coater (HCT Labo). The disintegration test (Pharmatest PTZ E) showedthat disintegration took place for 2 hr under pH 1.2.

As explained above, the present invention provides a new type ofpreparation method of water-dispersible hydroxypropyl methyl cellulosephthalate nanoparticle by preparing stable particle through introductionof aqueous emulsification process and regulating remaining electrolytecontent through ion exchange process. As a result, the present inventionresolves the environmental problem of the conventional method usingorganic solvent while maintaining basic properties of hydroxypropylmethyl cellulose phthalate. Therefore, it can be used as a new conceptfor environment-friendly enteric coating material.

1. A preparation method of solvent-free water-dispersible hydroxypropylmethyl cellulose phthalate nanoparticle comprising the steps of: 1)emulsifying hydroxypropyl methyl cellulose using an emulsifying agentand NH₄OH; and 2) regulating the remaining electrolyte content to 0-50mS using ion exchange resin or membrane.
 2. The preparation method ofsolvent-free water-dispersible hydroxypropyl methyl cellulose phthalatenanoparticle according to claim 1, wherein said step 1) is carried outat a temperature ranging from 20-70° C.
 3. The preparation method ofsolvent-free water-dispersible hydroxypropyl methyl cellulose phthalatenanoparticle according to claim 1, wherein said step 1) is carried outfor 4-6 hours.
 4. The preparation method of solvent-freewater-dispersible hydroxypropyl methyl cellulose phthalate nanoparticleaccording to claim 1, wherein the content of said emulsifying agent andNH₄₀OH in step 1) is 0.05-1.0 wt % and 1.6-4.0 wt % againsthydroxypropyl methyl cellulose phthalate, respectively.
 5. Thepreparation method of solvent-free water-dispersible hydroxypropylmethyl cellulose phthalate nanoparticle according to claim 1, whereinsaid ion exchange resin in step 2) is cation exchange resin and saidmembrane has pores of 100-300 nm in size.
 6. A water-dispersiblehydroxypropyl methyl cellulose phthalate prepared by the preparationmethod according to claim
 1. 7. The water-dispersible hydroxypropylmethyl cellulose phthalate according to claim 6, which has 100-1000 nmof particle size and 7-30 wt % of solids content.